Study of Sirolimus Therapy for Segmental Overgrowth Caused by Somatic PI3K Activation

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02428296
Recruitment Status : Completed
First Posted : April 28, 2015
Last Update Posted : October 11, 2018
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) )

Brief Summary:


- PIK3CA-related overgrowth spectrum (PROS) is caused by changes in the PIK3CA gene. This gene makes a protein that communicates with other proteins in the body to cause cells to grow. Alterations in PIK3CA change the chemical signals in the body and cause overgrowth in fatty, vascular and other tissues. Sirolimus is a drug that reduces the signals sent by one of the proteins in this chemical signaling pathway. Researchers want to learn whether the drug sirolimus can reduce or stabilize some of the overgrowth that patients with PROS experience.


- To measure how the overgrowth of patients with PROS changes over time and whether taking a drug called sirolimus can reduce or stabilize a person s overgrowth.


- People ages 3 to 65 years old with a confirmed mutation or alteration of the PIK3CA gene in the person s affected tissues (a somatic mutation).


  • Participants will be screened with medical history and genetic counseling.
  • First 6 months: Participants will have their overgrowth monitored.
  • Next 6 months: Participants will take sirolimus once or twice a day.
  • Participants will have to visit the clinic several times, and stay in the area for 4 5 days each time.
  • Participants will have a one month-long visit to the clinic.
  • During clinic visits, participants will have:
  • Blood and urine tests.
  • Photographs of their physical features.
  • Scans, including an MRI and DEXA, and possibly x-rays and CT scans.
  • For the MRI and CT scans, participants will lie in a machine that takes pictures of their body.
  • The DEXA involves a small amount of radiation.
  • They may have:
  • Non-invasive heart function tests.
  • Lung function tests.
  • Participants will have several blood and urine tests between visits.
  • Participants will complete surveys and keep a diary of their treatment and side effects.
  • Participants may visit other health specialists or undergo other tests based on side effects.
  • One month after stopping the study drug, participants will have 1 clinic visit.

Condition or disease Intervention/treatment Phase
PIK3CA-Related Overgrowth Spectrum (PROS) Growth Disorder Genetics Drug: Sirolimus Phase 2

Detailed Description:
The primary study objective is to determine the likely size of sirolimus treatment effect. The patient population will include male and female subjects, aged greater than or equal to 3 years and less than or equla to 65 years of age with segmental overgrowth identified to have clinical and molecular findings of somatic PIK3CA gene mutation. The planned study size will be ten patients seen at the NIHCC. An additional 20 patients will be contributed by two other centers, who will be responsible for the conduct of the proposed research at their site, but the study procedures and dosing schedule will be identical to enable pooling of results for statistical analyses. The study design will be a nonrandomized, open label, phase II pilot study of sirolimus treatment. As patients have highly variable clinical presentations, and there are no established evidence-based methodologies for measuring serial changes in growth, the aim of this pilot study is to establish the optimal methodology for evaluating changes in growth to inform the design of a future randomized controlled trial, in addition to determining treatment effect size, and evaluating safety and toxicity of low dose sirolimus. Overall desired outcome will be reduced size of affected body part, and measures will include: reduction in affected tissue (fibroadipose or bone) size by clinical exam measurement and by radiological studies (MRI area measurements and/or DXA study measurements of fat).

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Nonrandomized Open Label Pilot Study of Sirolimus Therapy for Segmental Overgrowth Caused by Somatic PI3K Activation
Study Start Date : April 23, 2015
Actual Primary Completion Date : February 14, 2018
Actual Study Completion Date : February 14, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Sirolimus

Intervention Details:
  • Drug: Sirolimus
    Low dose sirolimus will be given in daily dosing to achieve trough levels of 2-6 ng/ ml.

Primary Outcome Measures :
  1. The primary outcome measures will use quantitative MRI scan of the affected and unaffected body part (s) to demonstrate negativechange in fibrofatty, muscular, and/or bony overgrowth. [ Time Frame: At 0, 6, 9, 12 months ]
  2. A second primary outcome measure will evaluate use of Dual-energy Xray Absorptiometry (DXA) for body composition to demonstatereduction in fibrofatty overgrowth. [ Time Frame: At 0, 6, 9, 12 months ]
  3. The third primary outcome measure will evaluate the use of measurements on physical examination of affected body part(s). [ Time Frame: 0, 6, 6 1/2, 7, 9, 12 mos ]

Secondary Outcome Measures :
  1. To establish optimal sirolimus dosing algorithms for a future RCT. [ Time Frame: 12 mons ]
  2. To evaluate alternative treatment outcomes for inclusion as primary or secondary end-ppoints in a future RCT e.g. quality of life measures(both subjective and observational) in the pre- and post-treatment periods [ Time Frame: 0, 6, 7, 9, 12 mos ]
  3. To establish if inter-patient comparison will be feasible in a future RCT. [ Time Frame: 12 mons ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:   3 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
  • Age: greater than or equal to 3 years to less than or equal to 65 years
  • Male or Female
  • Confirmed PIK3CA somatic mutation
  • Measurably progressive overgrowth, in current progression or with clinical history of overgrowth progression
  • Adequate Bone Marrow Function Defined as:

    • Peripheral absolute neutrophil count (ANC) greater than or equal to 1500/microliter, except for those participants with an absolute neutrophil count (ANC) of 1000-1500, caused by a benign condition associated with moderately decreased neutrophils known as Benign Ethnic Neutropenia (BEN), d those who have an ANC of 1000-1500 caused by a confirmed infection, which resolves with treatment of infection to greater than or equal to 1500.
    • Platelet count less than or equal to 100,000/microliter
    • Hemoglobin less than or equal to 10.0 gm/dL
  • Adequate Renal Function Defined as:
  • A serum creatinine based on age as follows:

    • Age (years) [Maximum Serum Creatinine (mg/dl)]
    • Less than or equal to 5 [0.8 mg/dl]
    • 5 less than age less than or equal to10 [1.0 mg/dl]
    • 10 less than age less than or equal to 15 [1.2 mg/dl]
    • Less than 15 [1.5 mg/dl]
  • OR a creatinine clearance or radioisotope GFR greater than or equal to 70ml/min/1.73 m2

    • Adequate Liver Function Defined As:

      • Bilirubin (sum of conjugated + unconjugated) less than or equal to 1.5 x upper limit of normal (ULN) for age, and
      • SGPT (ALT) less than or equal to 5 x upper limit of normal (ULN) for age, and
      • Serum albumin greater than or equal to 2 g/dL.
    • Fasting LDL Cholesterol:

      • Patients must have a fasting LDL cholesterol of less than or equal to 160 mg/d
      • All women of childbearing potential and all sexually active male patients must agree to use effective contraception
      • Adolescent (15-17 year old) participants who are fluent in English and can thereby complete the pediatric self-report questionnaires and communicate well with the study team but whose parent(s) and/or legal guardian are primarily Spanish-speaking.


The participant may not enter the study if ANY of the following apply:

  • Age less than 3 years or greater than 65 years
  • Pregnant or breastfeeding
  • Women and men of reproductive age without an effective method of contraception (during treatment and up to 12 weeks after sirolimus discontinuation)
  • Hypersensitivity to sirolimus or any of the excipients
  • Any current medical disorder or medication likely to impair ability to follow the study protocol safely and effectively
  • Incapacity to give informed consent
  • Sirolimus treatment in the prior 4 weeks
  • If less than 3 months post-surgery
  • Prior malignancy or ongoing investigations for malignancy
  • Active skin infections requiring antibiotics or anti-viral medication
  • HCV/HBV/HIV seropositivity
  • Previous/ active MTB infection
  • Pneumonitis
  • Research radiation exposure within previous 12 months
  • Adult participants or participants under the age of 15 years with insufficient Englishlanguage proficiency to complete informed consent and quality of life measures

We propose to restrict participation in this study to those with sufficient English language skills to complete the quality of life measures we will employ among all three study sites, as many of the specific quality of life measures we are employing at the NIH only are not available in other languages.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02428296

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Human Genome Research Institute (NHGRI)
Principal Investigator: Kim M Keppler-Noreuil, M.D. National Human Genome Research Institute (NHGRI)

Additional Information:
Responsible Party: National Human Genome Research Institute (NHGRI) Identifier: NCT02428296     History of Changes
Other Study ID Numbers: 150120
First Posted: April 28, 2015    Key Record Dates
Last Update Posted: October 11, 2018
Last Verified: February 14, 2018

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) ):
Clinical Trial
Congenital Malformations
Pilot Drug Treatment Trial

Additional relevant MeSH terms:
Growth Disorders
Pathologic Processes
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs